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Antimicrob Agents Chemother. 2018 Oct 24;62(11). pii: e01356-18. doi: 10.1128/AAC.01356-18. Print 2018 Nov.

Reliable and Easy-To-Use Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantification of Olorofim (F901318), a Novel Antifungal Drug, in Human Plasma and Serum.

Author information

1
Centre of Pharmacology, Department of Therapeutic Drug Monitoring, University Hospital of Cologne, Cologne, Germany c.mueller@uni-koeln.de.
2
Centre of Pharmacology, Department of Therapeutic Drug Monitoring, University Hospital of Cologne, Cologne, Germany.
3
Department of Internal Medicine, University of Cologne, Cologne, Germany.
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
5
F2G Ltd., Manchester, United Kingdom.
6
Department of Clinical Chemistry, University Hospital of Cologne, Cologne, Germany.

Abstract

A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, olorofim (F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated. Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. An isotope-labeled analogue of F901318 was employed as an internal standard. Chromatographic separation was achieved using a 50-mm by 2.1-mm, 1.9-μm, polar Hypersil Gold C18 column and isocratic mobile phase consisting of 0.1% formic acid-acetonitrile (60%-40%, vol/vol) at a flow rate of 330 μl/min. The analyte was detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI+) within a single runtime of 2.00 min. The present LC-MS/MS method was validated according to the international guidelines of the International Conference on Harmonisation (ICH) and the U.S. Food and Drug Administration (FDA). Linearity of F901318 concentration ranges was verified by the Mandel test. The calibration curve was tested linear across the range and fitted using least-squares regression with a weighting factor of the reciprocal concentration. The limit of detection was 0.0011 mg/liter, and the lower limit of quantitation was 0.0033 mg/liter. Intraday and interday precisions ranged from 1.17% to 3.23% for F901318, and intraday and interday accuracies (percent bias) ranged from 0.75% to 5.01%. In conclusion, a method was established for the rapid quantitation of F901318 concentrations in serum and plasma samples in patient trials, and it optimizes therapeutic drug monitoring in applying an easy-to-use single method.

KEYWORDS:

antifungal agents; antifungal drug; liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS); matrix effects; orotomide; therapeutic drug monitoring

PMID:
30150474
PMCID:
PMC6201104
[Available on 2019-04-24]
DOI:
10.1128/AAC.01356-18

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